The biomechanical basis of biased epithelial tube elongation in lung and kidney development.

During lung development, epithelial branches expand preferentially in a longitudinal direction. This bias in outgrowth has been linked to a bias in cell shape and in the cell division plane. How this bias arises is unknown. Here, we show that biased epithelial outgrowth occurs independent of the surrounding mesenchyme, of preferential turnover of the extracellular matrix at the bud tips and of FGF signalling. There is also no evidence for actin-rich filopodia at the bud tips. Rather, we find epithelial tubes to be collapsed during early lung and kidney development, and we observe fluid flow in the narrow tubes. By simulating the measured fluid flow inside segmented narrow epithelial tubes, we show that the shear stress levels on the apical surface are sufficient to explain the reported bias in cell shape and outgrowth. We use a cell-based vertex model to confirm that apical shear forces, unlike constricting forces, can give rise to both the observed bias in cell shapes and tube elongation. We conclude that shear stress may be a more general driver of biased tube elongation beyond its established role in angiogenesis. This article has an associated 'The people behind the papers' interview.

Sustained response of galcanezumab in migraine prevention: Patient-level data from a post hoc analysis in patients with episodic or chronic migraine.

OBJECTIVE: To evaluate, at population and individual patient levels, the sustained response of reduction in migraine headache days in patients with migraine treated with galcanezumab. METHODS: This was a post hoc analysis of double-blind galcanezumab studies in patients with migraine: two 6-month episodic migraine (EM; EVOLVE-1/EVOLVE-2), one 3-month chronic migraine (CM; REGAIN), and one 3-month treatment-resistant migraine (CONQUER). Patients received monthly subcutaneous galcanezumab 120 mg (after 240 mg initial loading dose), galcanezumab 240 mg, or placebo. In the EM and CM studies, the proportions of patients with ≥50% and ≥75% (EM only) reduction from baseline in average monthly migraine headache days from Months 1 to 3 and Months 4 to 6 were evaluated. A mean monthly response rate was estimated. The sustained effect was defined as maintaining ≥50% response for ≥3 consecutive months in the patient-level data for EM and CM. RESULTS: A total of 3348 patients with EM or CM from the EVOLVE-1/EVOLVE-2 (placebo, n = 894, galcanezumab, n = 879), REGAIN (placebo, n = 558, galcanezumab, n = 555), and CONQUER (EM: placebo, n = 132, galcanezumab, n = 137; CM: placebo, n = 98, galcanezumab, n = 95) studies were included. Patients were predominantly female, White, and had monthly migraine headache day averages ranging from 9.1 to 9.5 days (EM) and 18.1 to 19.6 days (CM). In patients with EM and CM, 19.0% and 22.6% of galcanezumab-treated patients, respectively, had significantly higher maintenance of ≥50% response for all months in the double-blind period compared to 8.0% and 1.5% of placebo-treated patients. The odds ratios (OR) of achieving clinical response for EM and CM were double with galcanezumab (OR = 3.0 [95% CI 1.8, 4.8] and OR = 6.3 [95% CI 1.7, 22.7], respectively). At the individual patient level, of patients who had ≥75% response at Month 3 in the galcanezumab 120 and 240 mg dose groups and placebo group, 39.9% (55/138) and 43.0% (61/142), respectively, of galcanezumab-treated patients maintained ≥75% response during Months 4-6 compared to 32.7% (51/156) with placebo. CONCLUSION: More galcanezumab-treated patients achieved ≥50% response within the first 3 months of treatment compared to placebo; responses were sustained during Months 4-6. The odds of achieving ≥50% response were double with galcanezumab.

Global Overview of Response Rates in Patient and Health Care Professional Surveys in Surgery: A Systematic Review.

OBJECTIVE: Identify key demographic factors and modes of follow-up in surgical survey response. SUMMARY BACKGROUND DATA: Surveys are widely used in surgery to assess patient and procedural outcomes, but response rates vary widely which compromises study quality. Currently there is no consensus as to what the average response rate is and which factors are associated with higher response rates. METHODS: The National Library of Medicine (MEDLINE/PubMed) was systematically searched from Januray 1, 2007 until February 1, 2020 using the following strategy: (((questionnaire) OR survey) AND "response rate") AND (surgery OR surgical). Original survey studies from surgical(-related) fields reporting on response rate were included. Through one-way analysis of variance we present mean response rate per survey mode over time, number of additional contacts, country of origin, and type of interviewee. RESULTS: The average response is 70% over 811 studies in patients and 53% over 1746 doctor surveys. In-person surveys yield an average 76% response rate, followed by postal (65%) and online (46% web-based vs 51% email) surveys. Patients respond significantly more often than doctors to surveys by mail (P < 0.001), email (P = 0.003), web-based surveys (P < 0.001) and mixed mode surveys (P = 0.006). Additional contacts significantly improve response rate in email (P = 0.26) and web-based (P = 0.041) surveys in doctors. A wide variation in response rates was identified between countries. CONCLUSIONS: Every survey is unique, but the main commonality between studies is response rate. Response rates appear to be highly dependent on type of survey, follow-up, geography, and interviewee type.

Efficacy of lasmiditan for the acute treatment of perimenstrual migraine.

BACKGROUND: Perimenstrual migraine attacks in women with menstrual migraine is difficult to treat. This post-hoc analysis evaluated the efficacy of lasmiditan, a high affinity and selective 5-HT1F receptor agonist, for perimenstrual attacks. METHODS: Patients from two randomized, double-blind, placebo-controlled clinical trials (MONONOFU and CENTURION) were instructed to treat an attack with a single dose of study medication within four hours of pain onset. After dosing, the proportion of patients who achieved freedom from migraine-related head pain, most bothersome symptom, and disability was reported at baseline up to 48 hours after dose and pooled data were evaluated. RESULTS: A total of 303 patients (MONONOFU N = 78; CENTURION N = 225) treated perimenstrual migraine attacks with lasmiditan 50 mg (N = 24), 100 mg (N = 90), 200 mg (N = 110), and placebo (N = 79). More patients achieved migraine-related head pain freedom with lasmiditan 200 mg versus placebo at all time points assessed. At 2 hours, 33.6% of patients in the 200-mg group (p < 0.001), and 16.7% of patients in the 100-mg (p = 0.11) and 50-mg (p = 0.19) groups were pain free, compared with 7.6% in the placebo group. CONCLUSIONS: Lasmiditan treatment of perimenstrual migraine attacks was associated with freedom from migraine-related head pain at two hours, early onset of efficacy, and sustained efficacy.Clinical Trial registration: NCT03962738 and NCT03670810.

Can you have a migraine aura without knowing it?

PURPOSE OF REVIEW: This review covers several aspects our understanding of episodic manifestations and unusual symptoms that may be associated with migraine aura. RECENT FINDINGS: The episodic manifestation of migraine aura is typically visual in nature, although five other types are currently recognized: sensory, speech and/or language, motor, brainstem, and retinal. Other transitory perceptions or experiences such as emotional, olfactory, or auditory have been reported as possible migraine auras. As underlined by the much higher reported prevalence of aura manifestation in individuals with professional knowledge of its possible manifestations, it appears that a number of migraine auras may remain unnoticed, unreported, or misdiagnosed. SUMMARY: Aura manifestations may be more common, complex, symptom-rich and variable than previously thought. Clinicians should proactively ask questions beyond those addressing visual symptoms when examining individuals with a potential diagnosis of migraine with aura.

Neuroimaging clues of migraine aura.

While migraine headaches can be provoked, or predicted by the presence of an aura or premonitory symptoms, the prediction or elicitation of the aura itself is more problematic. Therefore, imaging studies directly examining the aura phenomenon are sparse. There are however interictal imaging studies that can shed light on the pathophysiology of the migraine with aura (MWA) cascade. Here, we review findings pointing to the involvement of cortical spreading depression (CSD) and neuroinflammation in MWA. Whether asymptomatic CSD also happens in some migraine without aura is still under debate. In addition, new evidence points to glial activation in MWA, indicating the involvement of astrocytes in the neuroinflammatory cascade that follows CSD, as well as dural macrophages, supporting the involvement of the trigeminovascular system in migraine pain.

Improving the detection of chronic migraine: Development and validation of Identify Chronic Migraine (ID-CM).

BACKGROUND: Migraine, particularly chronic migraine (CM), is underdiagnosed and undertreated worldwide. Our objective was to develop and validate a self-administered tool (ID-CM) to identify migraine and CM. METHODS: ID-CM was developed in four stages. (1) Expert clinicians suggested candidate items from existing instruments and experience (Delphi Panel method). (2) Candidate items were reviewed by people with CM during cognitive debriefing interviews. (3) Items were administered to a Web panel of people with severe headache to assess psychometric properties and refine ID-CM. (4) Classification accuracy was assessed using an ICHD-3ß gold-standard clinician diagnosis. RESULTS: Stages 1 and 2 identified 20 items selected for psychometric validation in stage 3 (n = 1562). The 12 psychometrically robust items from stage 3 underwent validity testing in stage 4. A scoring algorithm applied to four symptom items (moderate/severe pain intensity, photophobia, phonophobia, nausea) accurately classified most migraine cases among 111 people (sensitivity = 83.5%, specificity = 88.5%). Augmenting this algorithm with eight items assessing headache frequency, disability, medication use, and planning disruption correctly classified most CM cases (sensitivity = 80.6%, specificity = 88.6%). DISCUSSION: ID-CM is a simple yet accurate tool that correctly classifies most individuals with migraine and CM. Further testing in other settings will also be valuable.

Assessment of otoacoustic emission suppression in women with migraine and phonophobia.

Given that the medial olivocochlear efferent system reduces the amplitude of otoacoustic emissions (OAE), the aim of this study was to establish whether such a pathway is affected in women with migraine and phonophobia by means of OAE suppression testing. In this prospective case-control study, 55 women (29 with migraine and phonophobia and 26 healthy women) were subjected to transient-evoked otoacoustic emission (TEOAE) testing at frequencies from 1 to 4 kHz. The amplitudes of the TEOAE response before and after exposure to contralateral noise and the magnitude of TEOAE suppression were assessed. The average TEOAE amplitudes in conditions with and without exposure to contralateral noise were not significantly different between the groups. However, the magnitude of TEOAE suppression was lower in the group with migraine; that difference was only statistically significant for frequencies 1 and 1.5 kHz (p = 0.042 and p = 0.004, respectively). In this study, women with migraine and phonophobia exhibited deficits in OAE suppression, which points to a disorder affecting the medial olivocochlear efferent system.

Vision and migraine.

BACKGROUND: Migraine, a common brain disorder, disrupts vision more than any other motor or sensory function. The possible visual aura symptoms vary from occasional small flashes of light to complex visual hallucinations, the stereotyped teichopsia being the most typical pattern. It is unclear as to why aura occurs serendipitously, sometimes preceding, but also occurring after the headache, and why aura can present with multiple phenotypes. METHODS: To better understand the nature of visual disturbances in migraine, 4 aspects must be considered: What are the visual perceptions in migraine; why vision is affected in migraine; the role of cortical spreading depression (CSD); how does vision could affect migraine. Evidence supporting each of these topics is reviewed. RESULTS: CSD travels at a similar pace as the march of symptoms in the visual field. Functional neuroimaging studies show spreading changes compatible with CSD regardless of aura. Computerized models reproducing the CSD march on the visual cortex predict a sensory experience compatible with naturally occurring visual auras. Rather than spreading in all directions, these models suggest that CSD moves preferentially in one direction. Migraine-preventive drugs increase the CSD threshold and reduce CSD velocity. Blind migraineurs may present atypical visual aura, with more colors, shorter duration, different shapes, and atypical symptoms, such as auditory experiences. CONCLUSIONS: CSD is the underlying phenomenon in migraine with and without aura. In migraine without aura, CSD probably does not run over silent areas of the cortex, but rather does not reach symptomatology threshold. Normal vision is important in migraine, as lack of sight may change the visual experience during migraine aura, probably due to cortical reorganization and changes in local susceptibility to CSD.

Decision-making in classic trigeminal neuralgia concurrent with a pontine cavernous malformation: Causal or coincidental association?

Trigeminal neuralgia is classically associated with neurovascular compression of the trigeminal nerve, at the root entry zone (REZ). However, patients are occasionally affected by intra-axial involvement of trigeminal sensory fibers caused by demyelinating diseases, strokes and, rarely, pontine cavernous malformations. We discuss the management strategies and decision-making process in a 55-year-old patient, affected by trigeminal neuralgia with 2 potential causative mechanisms: a neurovascular conflict at the trigeminal REZ and an ipsilateral cavernous malformation at the pontine nucleus of the trigeminal nerve.

Cuneus and fusiform cortices thickness is reduced in trigeminal neuralgia.

BACKGROUND: Chronic pain disorders are presumed to induce changes in brain grey and white matters. Few studies have focused CNS alterations in trigeminal neuralgia (TN). METHODS: The aim of this study was to explore changes in white matter microstructure in TN subjects using diffusion tensor images (DTI) with tract-based spatial statistics (TBSS); and cortical thickness changes with surface based morphometry. Twenty-four patients with classical TN (37-67 y-o) and 24 healthy controls, matched for age and sex, were included in the study. RESULTS: Comparing patients with controls, no diffusivity abnormalities of brain white matter were detected. However, a significant reduction in cortical thickness was observed at the left cuneus and left fusiform cortex in the patients group. The thickness of the fusiform cortex correlated negatively with the carbamazepine dose (p = 0.023). CONCLUSIONS: Since the cuneus and the fusiform gyrus have been related to the multisensory integration area and cognitive processing, as well as the retrieval of shock perception conveyed by Aδ fibers, our results support the role of these areas in TN pathogenesis. Whether such changes occurs as an epiphenomenon secondary to daily stimulation or represent a structural predisposition to TN in the light of peripheral vascular compression is a matter of future studies.

Hemicrania continua. Unquestionably a trigeminal autonomic cephalalgia.

Hemicrania continua (HC) is a well-known primary headache. The present version of the International Classification of Headache Disorders lists HC in the "other primary headaches" group. However, evidence has emerged demonstrating that HC is a phenotype that belongs to the trigeminal autonomic cephalalgias together with cluster headache, paroxysmal hemicrania (PH), and short-lasting, unilateral neuralgiform headache attacks with conjunctival injection and tearing. This is supported by a common general clinical picture - paroxysmal, fluctuating, unilateral, side-locked headaches located to the ocular, frontal, and/or temporal regions, accompanied by ipsilateral autonomic dysfunctions including for example, tearing and conjunctival injection. Apart from the remarkable clinical similarities, the absolute and incomparable effect of indomethacin in HC parallels the effect of this drug in PH, suggesting a shared core pathogenesis. Finally, neuroimage findings demonstrate a posterior hypothalamic activation in HC similarly to cluster headache, PH, and short-lasting, unilateral neuralgiform headache attacks with conjunctival injection and tearing. Taken together, data indicate that HC is certainly a type of trigeminal autonomic cephalalgia that should no longer be placed in a group of miscellaneous primary headache disorders.

The role of the cerebellopontine angle cistern area and trigeminal nerve length in the pathogenesis of trigeminal neuralgia: a prospective case-control study.

BACKGROUND: The aim of this prospective study was to evaluate whether the cerebellopontine angle (CPA) cistern area and trigeminal nerve cisternal length play a role in the pathogenesis of trigeminal neuralgia (TN). METHODS: High-resolution 1.5 T magnetic resonance imaging of the posterior fossa was performed in 26 patients with TN and 18 age-matched healthy controls. Axial T2-weighted, three-dimensional constructive interference in steady-state (3D-CISS) was used to measure bilaterally the cross-sectional area of the CPA cistern and trigeminal nerve cisternal length. RESULTS: In patients, the cross-sectional area of the CPA cistern and trigeminal nerve cisternal length was smaller on the affected side (p = 0.04). Healthy controls tended to have larger cisternal areas and longer trigeminal nerve lengths than patients (p = 0.059, p = 0.071, respectively). Larger CPA cisternal areas tended to be seen in older patients. There was a strong correlation between the cross-sectional area of the CPA cistern and the length of the trigeminal nerve (p = 0.000). CONCLUSIONS: Smaller CPA cisterns and short cisternal trigeminal nerves impact the pathogenesis of essential TN by facilitating the neurovascular conflict, especially in younger patients. Trigeminal nerve cisternal measurement provides an easy and direct estimation of the CPA area. This information can be used for surgical planning and potentially for outcome prediction.

Serotonin syndrome in the acute treatment landscape of migraine: the lasmiditan experience.

Background: Serotonin syndrome (SS) symptoms overlap with adverse events associated with lasmiditan, a 5-HT (serotonin)1F receptor agonist for acute treatment of migraine. Because SS symptoms are heterogeneous, diagnosis can be challenging, and potential cases observed with lasmiditan treatment led to questions about SS pathophysiology. Here, we provide an overview of the potential risk of SS based on experience with lasmiditan. Methods: Results of eight phase 2 and phase 3 lasmiditan trials (n = 5,916) and a controlled intravenous trial of lasmiditan (n = 88) were analyzed for symptomatology consistent with SS. Post-marketing surveillance data from lasmiditan's US launch date (January 2020) until data cut-off (April 2021) were also examined. Established Sternbach and Hunter diagnostic criteria were used for formal determination of SS. Results: Of 6,004 lasmiditan-treated clinical trial patients, 15 reported ≥1 treatment-emergent adverse event consistent with signs and symptom(s) of SS. After review, one case met Sternbach and Hunter criteria, two cases potentially met Sternbach criteria, and three cases reported as SS had limited/no information to determine if either criterion was met. During post-marketing surveillance (approximately 13,400 lasmiditan prescriptions), 17 cases with symptom complexes consistent with SS were reported; 3/17 cases had adequate case descriptions to apply predefined criteria. Of these, two met Sternbach and Hunter criteria, and one met Sternbach criteria. Conclusion: Awareness of clinical symptomatology and diagnostic criteria of SS can help clinicians with recognition of rare instances of SS that may occur with lasmiditan. Clinical trial registration: NCT03670810, NCT00384774, NCT00883051, NCT02565186.

Reduced basal ganglia µ-opioid receptor availability in trigeminal neuropathic pain: a pilot study.

BACKGROUND: Although neuroimaging techniques have provided insights into the function of brain regions involved in Trigeminal Neuropathic Pain (TNP) in humans, there is little understanding of the molecular mechanisms affected during the course of this disorder. Understanding these processes is crucial to determine the systems involved in the development and persistence of TNP. FINDINGS: In this study, we examined the regional µ-opioid receptor (µOR) availability in vivo (non-displaceable binding potential BPND) of TNP patients with positron emission tomography (PET) using the µOR selective radioligand [11C]carfentanil. Four TNP patients and eight gender and age-matched healthy controls were examined with PET. Patients with TNP showed reduced µOR BPND in the left nucleus accumbens (NAc), an area known to be involved in pain modulation and reward/aversive behaviors. In addition, the µOR BPND in the NAc was negatively correlated with the McGill sensory and total pain ratings in the TNP patients. CONCLUSIONS: Our findings give preliminary evidence that the clinical pain in TNP patients can be related to alterations in the endogenous µ-opioid system, rather than only to the peripheral pathology. The decreased availability of µORs found in TNP patients, and its inverse relationship to clinical pain levels, provide insights into the central mechanisms related to this condition. The results also expand our understanding about the impact of chronic pain on the limbic system.

Controversy over the classification of medication-overuse headache.

Medication-overuse headache (MOH) is a relatively common and impactful disorder, affecting 1% to 2% of the population, characterized by daily or near-daily headache aggravated by chronic acute medication intake. Primary headache patients do not necessarily develop MOH after acute medication overuse, although a pre-existing primary headache is inevitably present. Likewise, headache patients may deteriorate in terms of frequency without medication overuse, or suffer from chronic headache in the presence of drug abuse without any causal relationship. To classify and define diagnostic criteria for MOH in the absence of objective biomarkers is a difficult task that is presently based on clinical grounds and is limited in part by the relative lack of research in this field. The present criteria are less restrictive but also less precise than the previous versions because they allow the diagnosis without the previously required MOH confirmation after medication withdrawal. MOH should remain as a distinct secondary disorder based on the available clinical and pathophysiological evidence.

Lasmiditan for Patients with Migraine and Contraindications to Triptans: A Post Hoc Analysis.

INTRODUCTION: As 5-HT1B receptor agonists, triptans produce vasoconstriction and have cardiovascular contraindications and precautions. Lasmiditan, a selective 5-HT1F receptor agonist, has a low affinity for 5-HT1B receptors, does not cause vasoconstriction, and is free of cardiovascular contraindications and precautions. The objective of this post hoc analysis was to evaluate the efficacy and safety of lasmiditan in patients with and without at least one triptan contraindication. METHODS: Patient subgroups, with and without triptan contraindications, were analyzed from pooled patient data from four randomized, double-blind, placebo-controlled clinical trials (SAMURAI, SPARTAN, CENTURION, and MONONOFU). Patients experiencing a single migraine attack of moderate or severe intensity were treated with lasmiditan 50 mg (SPARTAN and MONONOFU only), 100 mg, 200 mg, or placebo, and efficacy data were recorded in an electronic diary. RESULTS: Of 5704 patients, 207 (3.6%) patients had at least one contraindication to triptans. Overall subgroup analysis revealed that the effects of lasmiditan on pain freedom, pain relief, freedom from most bothersome symptom, disability freedom, and Patient Global Impression of Change at 2 h post-dose did not differ in patient groups with and without triptan contraindications. These outcomes generally showed a similar benefit pattern for lasmiditan in both subgroups, with all results being statistically significant in patients without contraindications, and pain relief being statistically significant in patients with contraindications. The safety and tolerability profiles of patients with triptan versus without triptan contraindications were similar, including dizziness in 18.3 to 22.8% and somnolence in 7.9 to 9.9% of patients at the highest dose of lasmiditan. CONCLUSIONS: In pooled analyses from four trials, patients with and without triptan contraindications did not differ in their patterns of lasmiditan efficacy. Lasmiditan may be a treatment option in patients with contraindications to triptans. TRIAL REGISTRATION NUMBERS: SAMURAI, NCT:02439320; SPARTAN, NCT:02605174; CENTURION, NCT:03670810; and MONONOFU, NCT:03962738.

Potential Channeling Bias in the Evaluation of Cardiovascular Risk: The Importance of Comparator Selection in Observational Research.

BACKGROUND: Comparator selection is an important consideration in the design of observational research studies that evaluate potential associations between drug therapies and adverse event risks. It can affect the validity of observational study results, and potentially impact data interpretation, regulatory decision making, and patient medication access. OBJECTIVE: The aim of this study was to assess the impact of comparator selection bias using two real-world case studies evaluating an increased rate of acute myocardial infarction (AMI). METHODS: Data from the Truven Health Analytics MarketScan® electronic medical claims database were used to conduct two retrospective observational cohort studies, utilizing a cohort new-user design, comparing AMI risk between testosterone replacement therapy (TRT) and phosphodiesterase-5 inhibitors (PDE5is) in men treated for hypogonadism, and triptans versus other prescribed acute treatments for migraine in adults. All patients were enrolled continuously in a health plan (no enrollment gap > 31 consecutive days) for ≥ 1 year before index. Baseline period was defined as 365 days prior to index. Exposure was defined by prescription and outcome of interest was defined as occurrence of AMI. Using Cox proportional hazard models, primary analysis for the TRT cohort compared AMI risk between propensity score (PS)-matched TRT-treated and untreated patients; secondary analysis evaluated risk between PS-matched TRT-treated and PDE5i-treated patients. For the triptan cohort, primary analysis compared AMI/ischemic stroke risk between PS-matched triptan-treated and opiate-treated patients; secondary analysis evaluated risk between PS-matched triptan-treated and nonsteroidal anti-inflammatory drug (NSAID)-treated patients and PS-matched non-prescription-treated migraine patients and general patients. RESULTS: No significant association between TRT and AMI was observed among TRT-treated (N = 198,528, mean age 52.4 ± 11.4 years) versus PDE5i-treated men (N = 198,528, mean age 52.3 ± 11.5 years) overall (adjusted hazard ratio [aHR] 1.01; 95% CI 0.95-1.07; p = 0.80). Among patients with prior cardiovascular disease (CVD), risk of AMI was significantly increased for TRT-treated versus PDE5i-treated patients (aHR 1.13; 95% CI 1.03-1.25). The triptan study included three comparisons (triptans [N = 436,642] vs prescription NSAIDs [N = 334,152], opiates [N = 55,234], and untreated migraine [N = 1,168,212]), and a positive control (untreated vs general non-migraine patients [N = 11,735,009]). Analyses of MI risk in migraine patients prescribed triptans versus NSAIDs/opiates had mixed results: the point estimate ranged from 0.33 to 0.84 depending on chosen study window. CONCLUSIONS: Cardiovascular outcomes were not worse in hypogonadism patients with TRT versus PDE5i; however, a potential association with AMI was found in patients with prior CVD receiving TRT versus PDE5i. Findings pointed to a pseudo-protective effect of triptans versus untreated migraine patients or those potentially older and less healthy patients exposed to prescription NSAIDs or opiates. Triptan users should not be compared with those using other anti-migraine prescriptions when evaluating cardiovascular outcomes in migraine patients. Presence of high cardiovascular risks may contribute to channeling bias-healthier subjects being selected to receive treatment-highlighting the importance of choosing comparators wisely in observational studies.

The not so hidden impact of interictal burden in migraine: A narrative review.

Migraine is a highly prevalent neurological disease of varying attack frequency. Headache attacks that are accompanied by a combination of impact on daily activities, photophobia and/or nausea are most commonly migraine. The headache phase of a migraine attack has attracted more research, assessment tools and treatment goals than any other feature, characteristic, or phase of migraine. However, the migraine attack may encompass up to 4 phases: the prodrome, aura, headache phase and postdrome. There is growing recognition that the burden of migraine, including symptoms associated with the headache phase of the attack, may persist between migraine attacks, sometimes referred to as the "interictal phase." These include allodynia, hypersensitivity, photophobia, phonophobia, osmophobia, visual/vestibular disturbances and motion sickness. Subtle interictal clinical manifestations and a patient's trepidation to make plans or commitments due to the unpredictability of migraine attacks may contribute to poorer quality of life. However, there are only a few tools available to assess the interictal burden. Herein, we examine the recent advances in the recognition, description, and assessment of the interictal burden of migraine. We also highlight the value in patients feeling comfortable discussing the symptoms and overall burden of migraine when discussing migraine treatment needs with their provider.

The digiti quinti sign in hemiplegic migraine: An fMRI study.

BACKGROUND AND PURPOSE: The digiti quinti sign (DQS) consists of a wider angle between the fourth and fifth fingers (ANG) indicative of subtle hemiparesis that has been found interictally in hemiplegic migraine (HM), suggesting a permanent subtle motor dysfunction. The aim of this study was to find a possible cortical origin for the DQS using blood oxygen level dependent (BOLD) functional (f) MRI. METHODS: Eight HM patients and 13 controls entered the cross-sectional study. We examined hand dominance, performed handgrip tests with dynamometry, documented the DQS graphically in two consecutive sessions, and used BOLD-fMRI during a motor task specifically designed to measure the evoked activation in the motor cortex (M1). The brain activation at the symptomatic side was compared with the contralateral hemisphere and with both correspondent hemispheres in controls. RESULTS: Subjects had a normal neurological examination, except for DQS in all HM patients. The activation amplitude (beta values) and the cluster extension (mm3 ) of the activation area in M1 was smaller at the affected side. Besides, the cluster extension correlated negatively with the disease time span. The ANG was wider bilaterally in patients and the fMRI signals were reduced in the patient's group. CONCLUSION: The DQS, a relevant clinical finding in HM, indicates a disrupted cortical activation.